The Unit for Systems Neuroscience in Psychiatry (SNP) of the Clinical Brain Disorders Branch consists of multidisciplinary specialists with expertise in multimodal imaging techniques. SNP pursues research using a variety of techniques such as functional and structural neuroimaging and transcranial magnetic stimulation to understand brain circuits that are important for cognitive function, social behavior, and risk for severe mental illness, such as schizophrenia. Over the last year the group has focused on characterizing the mechanism of action of genetic contributions to psychiatric disorders. To accomplish this, we first identify candidate genes then begin the daunting task toward understanding how genetic variation(s) in the gene influences the complex mental and social phenomenon that occur in mental illness. Neuroimaging methods enable us to characterize the impact of genetic variation on functional brain circuits that are important for working memory, episodic memory, regulation of emotion and social cognition. This is how we will begin to understand the mechanisms which translate into genetic effects for risk for mental illness. In a study characterizing brain circuits for social behavior, the group examined the effects of administering oxytocin, a neuropeptide which is known to reduce anxiety and impacts fear conditioning and extinction in humans. Recent studies have shown that oxytocin increases trust suggesting amygdala involvement which expresses a high concentration of oxytocin receptors in many mammals. Using fear-inducing visual stimuli, our data show that human amygdala function is strongly modulated by oxytocin. Results indicate a neural mechanism for the effects of oxytocin in social cognition in the human brain. Another study looked at allelic variation in the monoamine oxidase A (MAOA) gene associated with impulsive aggression in animals and humans. We studied the impact of a common functional polymorphism in MAOA in brain structure and function of healthy subjects. In the face matching task we found that the low expression variant, associated with increased risk for violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala as compared with the high expression allele. The group also reviewed the current advances for examining the functional and structural neural mechanisms specifically altered in Williams syndrome (WS) a neurodevelopmental disorder caused by a hemizygous deletion of approximately 28 genes on chromosome 7. We have identified specific neural mechanisms that are more than likely associated to the unique behavioral phenotype, hypersociability and anxiety towards non-social objects, of this condition. Data have consistently shown that WS is the result of complex interplay between these altered neural systems most likely during brain development. Our continued research will delve into a more detailed mechanistic inquiry of specific mechanisms for executive and social cognition by examining individual genes and gene-gene interactions using animal models and special populations. In addition, we hope to pursue developmental studies which investigate the time course for the emergence of WS and modifications of altered neural circuitry. Because this rare condition offers an unprecedented view into the genetic mechanisms underlying complex behavior, the potential research and clinical impact will extend beyond those with WS. The group tackled the problem of ill-defined schizophrenia intermediate phenotypes by invoking a neuroimaging approach to examine the contribution of several potentially functional variants in a gene (i.e. COMT) and haplotypes to the risk of schizophrenia. Imaging genetics allowed us to evaluate the functional impact of these haplotypes on a neural system-level intermediate phenotype in healthy controls during a working memory task. Our data shows that complex genetic variation can be validated functionally in humans and linked to prefrontal inefficiency. In a recent review looking at subtle gene effects which may be invisible through traditional clinical and psychometric measures, imaging-genetics has elucidated the contribution of COMT, GRM3, G72, DISC1, and BDNF to cognitive deficits in schizophrenia. These data suggest there are common mechanisms underlying susceptibility for schizophrenia associated with complex genetic variations. Lastly, we explored the neurophysiological correlates of age-related reduction in working memory (WM) capacity. We found that within working memory capacity the elderly reached their limitation sooner as the younger subjects. Normal aging is associated with a decrease in neural efficiency and that the elderly need to recruit more units of resources even at lower levels of difficulty to maintain proficiency in task performance. As cognitive demand increases, they are pushed beyond a threshold beyond which any additional resources can be recruited. This leads to a decline in performance. Studies are being pursued to explore the effect of aging on other brain systems, and the role of genetics on these changes.